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Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor

¹Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences; ²Division of Endocrinology and Metabolism, Department of Medicine, and ³Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32611; and ⁴Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720

Submitted 1 August 2003 ; accepted in final form 30 September 2003

Hyperhomocysteinemia in humans is associated with genetic variants of several enzymes of folate and one-carbon metabolism and deficiencies of folate and vitamins B₁₂ and B₆. In each case, hyperhomocysteinemia might be caused by diminished folate-dependent homocysteine remethylation, but this has not been confirmed in vivo. Because published stable isotopic tracer approaches cannot distinguish folate-dependent from folate-independent remethylation, we developed a dual-tracer procedure in which a [U-¹³C₅]-methionine tracer is used in conjunction with a [3-¹³C]serine tracer to simultaneously measure rates of total and folate-dependent homocysteine remethylation. In young female subjects, plasma [U-¹³C₄]homocysteine enrichment, a surrogate measure of intracellular [U-¹³C₅]methionine enrichment, reached 90% of the plasma [U-¹³C₅]methionine enrichment. Methionine-methyl and -carboxyl group fluxes were in the range of previous reports (25 and 17 µmol·kg^–1·h^–1, respectively). However, the rate of overall homocysteine remethylation (8 µmol·kg^–1·h^–1) was twice that of previous reports, which suggests a larger role for homocysteine remethylation in methionine metabolism than previously thought. By use of estimates of intracellular [3-¹³C]serine enrichment based on a conservative correction of plasma [3-¹³C]serine enrichment, serine was calculated to contribute 100% of the methyl groups used for total body homocysteine remethylation under the conditions of this protocol. This contribution represented only a small fraction (2.8%) of total serine flux. Our dual-tracer procedure is well suited to measure the effects of nutrient deficiencies, genetic polymorphisms, and other metabolic perturbations on homocysteine synthesis and total and folate-dependent homocysteine remethylation.

methionine; methylation cycle; cystathionine

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